Molecular insights into human brain evolution

Rapidly advancing knowledge of genome structure and sequence enables new means for the analysis of specific DNA changes associated with the differences between the human brain and that of other mammals. Recent studies implicate evolutionary changes in messenger RNA and protein expression levels, as well as DNA changes that alter amino acid sequences. We can anticipate having a systematic catalogue of DNA changes in the lineage leading to humans, but an ongoing challenge will be relating these changes to the anatomical and functional differences between our brain and that of our ancient and more recent ancestors.     

Genome sequence of the Brown Norway rat yields insights into mammalian evolution

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.     

Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments.

Progressive cerebral deposition of the amyloid beta-peptide is an early and invariant feature of Alzheimer's disease. The beta-peptide is released by proteolytic cleavages from the beta-amyloid precursor protein (beta APP), a membrane-spanning glycoprotein expressed in most mammalian cells. Normal secretion of beta APP involves a cleavage in the beta-peptide region, releasing the soluble extramembranous portion and retaining a 10K C-terminal fragment in the membrane. Because this secretory pathway precludes beta-amyloid formation, we searched for an alternative proteolytic processing pathway that can generate beta-peptide-bearing fragments from full-length beta APP. Incubation of living human endothelial cells with a beta APP antibody revealed reinternalization of mature beta APP from the cell surface and its targeting to endosomes/lysosomes. After cell-surface biotinylation, full-length biotinylated beta APP was recovered inside the cells. Purification of lysosomes directly demonstrated the presence of mature beta APP and an extensive array of beta-peptide-containing proteolytic products. Our results define a second processing pathway for beta APP and suggest that it may be responsible for generating amyloid-bearing fragments in Alzheimer's disease.     

New insights into mTOR structure and regulation

The mammalian target of rapamycin, mTOR, forms various protein-protein complexes to regulate cell growth in response to the nutrient and energy status of the cell. Recently, the first crystal structure of large HEAT repeat protein mTOR revealed that the FAT domain interacts with the kinase domain through electrostatic effects and hydrophobic interactions. Based on the structure, the previous researches on how FAT domain regulates mTOR activity are reviewed. DEPTOR is currently known as an endogenous mTOR inhibitor, which may interact with roTOR FAT domain to suppress mTOR activity in vivo. The possible interactions of DEPTOR with the mTOR FAT domain are analyzed, too. In addition, the inhibition mechanism of DEPTOR may be similar to members of HEAT-involved RanGTP complex family, providing new mechanistic insights into mTOR kinase regulation.     

New insights into the properties of high-manganese steel

In the Collaborative Research Centre 761's Steel ab initio-quantum mechanics guided design of new Fe based materials, scientists and engineers from RWTH Aachen University and the Max Planck Institute for Iron Research conducted research on mechanism-controlled material development with a particular focus on high-manganese alloyed steels. From 2007 to 2019, a total of 55 partial projects and four transfer projects with industrial participation(some running until 2021) have studied material and process design as well as material characterization. The basic idea of the Collaborative Research Centre was to develop a new methodological approach to the design of structural materials. This paper focuses on selected results with respect to the mechanical properties of high-manganese steels, their underlying physical phenomena, and the specific characterization and modeling tools used for this new class of materials. These steels have microstructures that require characterization by the use of modern methods at the nm-scale. Along the process routes, the generation of segregations must be taken into account. Finally, the mechanical properties show a characteristic temperature dependence and peculiarities in their fracture behavior. The mechanical properties and especially bake hardening are affected by short-range ordering phenomena. The strain hardening can be adjusted in a never-before-possible range, which makes these steels attractive for demanding sheet-steel applications.     

New insights into the properties of high-manganese steel

In the Collaborative Research Centre 761’s“Steel ab initio-quantum mechanics guided design of new Fe based materials,”scientists and engineers from RWTH Aachen University and the Max Planck Institute for Iron Research conducted research on mechanism-controlled material development with a particular focus on high-manganese alloyed steels.From 2007 to 2019,a total of 55 partial projects and four transfer projects with industrial participation(some running until 2021)have studied material and process design as well as material characterization.The basic idea of the Collaborative Research Centre was to develop a new methodological approach to the design of structural materials.This paper focuses on selected results with respect to the mechanical properties of high-manganese steels,their underlying physical phenomena,and the specific characterization and modeling tools used for this new class of materials.These steels have microstructures that require characterization by the use of modern methods at the nm-scale.Along the process routes,the generation of segregations must be taken into account.Finally,the mechanical properties show a characteristic temperature dependence and peculiarities in their fracture behavior.The mechanical properties and especially bake hardening are affected by short-range ordering phenomena.The strain hardening can be adjusted in a never-before-possible range,which makes these steels attractive for demanding sheet-steel applications.     

Multiple D2 dopamine receptors produced by alternative RNA splicing

Dopamine receptor belong to a large class of neurotransmitter and hormone receptors that are linked to their signal transduction pathways through guanine nucleotide binding regulatory proteins (G proteins). Pharmacological, biochemical and physiological criteria have been used to define two subcategories of dopamine receptors referred to as D1 and D2. D1 receptors activate adenylyl cyclase and are coupled with the Gs regulatory protein. By contrast, activation of D2 receptors results in various responses including inhibition of adenylyl cyclase, inhibition of phosphatidylinositol turnover, increase in K+ channel activity and inhibition of Ca2+ mobilization. The G protein(s) linking the D2 receptors to these responses have not been identified, although D2 receptors have been shown to both copurify and functionally reconstitute with both Gi and Go related proteins. The diversity of responses elicited by D2-receptor activation could reflect the existence of multiple D2 receptor subtypes, the identification of which is facilitated by the recent cloning of a complementary DNA encoding a rat D2 receptor. This receptor exhibits considerable amino-acid homology with other members of the G protein-coupled receptor superfamily. Here we report the identification and cloning of a cDNA encoding an RNA splice variant of the rat D2 receptor cDNA. This cDNA codes for a receptor isoform which is predominantly expressed in the brain and contains an additional 29 amino acids in the third cytoplasmic loop, a region believed to be involved in G protein coupling.     

Structural insights into the stereochemistry of the cyclooxygenase reaction

Cyclooxygenases are bifunctional enzymes that catalyse the first committed step in the synthesis of prostaglandins, thromboxanes and other eicosanoids. The two known cyclooxygenases isoforms share a high degree of amino-acid sequence similarity, structural topology and an identical catalytic mechanism. Cyclooxygenase enzymes catalyse two sequential reactions in spatially distinct, but mechanistically coupled active sites. The initial cyclooxygenase reaction converts arachidonic acid (which is achiral) to prostaglandin G2 (which has five chiral centres). The subsequent peroxidase reaction reduces prostaglandin G2 to prostaglandin H2. Here we report the co-crystal structures of murine apo-cyclooxygenase-2 in complex with arachidonic acid and prostaglandin. These structures suggest the molecular basis for the stereospecificity of prostaglandin G2 synthesis.     

Translating insights from the cancer genome into clinical practice

Cancer cells have diverse biological capabilities that are conferred by numerous genetic aberrations and epigenetic modifications. Today's powerful technologies are enabling these changes to the genome to be catalogued in detail. Tomorrow is likely to bring a complete atlas of the reversible and irreversible alterations that occur in individual cancers. The challenge now is to work out which molecular abnormalities contribute to cancer and which are simply 'noise' at the genomic and epigenomic levels. Distinguishing between these will aid in understanding how the aberrations in a cancer cell collaborate to drive pathophysiology. Past successes in converting information from genomic discoveries into clinical tools provide valuable lessons to guide the translation of emerging insights from the genome into clinical end points that can affect the practice of cancer medicine.     

Structural insights into phosphoinositide 3-kinase catalysis and signalling

Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual-specificity enzymes with a lipid kinase activity which phosphorylates phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P, are second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking. Here we report the 2.2 A X-ray crystallographic structure of the catalytic subunit of PI3Kgamma, the class I enzyme that is activated by heterotrimeric G-protein betagamma subunits and Ras. PI3Kgamma has a modular organization centred around a helical-domain spine, with C2 and catalytic domains positioned to interact with phospholipid membranes, and a Ras-binding domain placed against the catalytic domain where it could drive allosteric activation of the enzyme.     

视觉信息加工及其脑机制

 视觉是人们感知外部世界最重要的途径之一。视觉信号通过视网膜接收后传递到大脑皮层进行加工处理,最终形成人们所意识到的画面。目前为止,已有大量研究从不同水平不同角度探讨大脑如何对视觉信息进行加工和表征,但仍有很多未解的问题。本文综述了视觉信息加工的研究进展,回顾了脑视觉信息加工过程及组织形式,总结了近年来有关视觉可塑性、知觉学习、生物社会信息知觉等方面的研究进展。